This is an omnibus project that covers a variety of studies on development, validation, refinement, and applications of methods to determine basic biochemical and physiological mechanisms underlying the regulation of cerebral blood flow (CBF) and energy metabolism at rest and in response to functional activation. Studies completed and published this year have shown that ATP-sensitive K+ ion channels, which exist in vascular smooth muscle and serve to relax the muscle producing vasodilatation, do not contribute to the increases in CBF associated with neuronal functional activation. Also, other studies completed this year and in press have disproved the hypothesis that dopamine receptors are involved in the functional activation of CBF. Studies completed this year have confirmed that there is a compartmentalization of glucose metabolism between astroglia and neurons. The astroglia metabolize glucose to lactate and export it to neurons which oxidize it to CO2 and H2O. These studies showed that neurons readily oxidize both glucose and lactate but have a kinetic preference to oxidize lactate derived from the extracellular space over pyruvate/lactate produced intracellularly by glycolysis. Astroglia also can oxidize both glucose and lactate to CO2, but they do so sparingly, and they metabolize glucose mainly to lactate. The limited ability of the astroglia is due to limited pyruvic dehydrogenase (PDH) activity. This enzyme exists in astroglia predominantly in the phosphorylated inactive form, but it can be activated by dichloroacetate, which we found can stimulate astroglia to oxidize lactate and diminish their export of lactate to neurons. When administered in vivo to rats, it produced no obvious changes in gross behavior and led to increases in cerebral glucose utilization, presumably due to increased utilization of glucose to compensate for the diminished import of lactate from the astroglia. The conclusion from these studies is that the compartmentalization of glucose metabolism between neurons and astroglia does exist, but it is neither complete nor obligatory. Studies on two strains of mutant mice with either the alpha or the beta thyroid receptor genetically altered so that they could not bind L-triiodothyronine are still in progress. Part of the results were published this year. Cerebral glucose utilization was found to be completely normal in the mice with the altered beta thyroid hormone receptor, but was markedly and diffusely depressed in the mice with the dysfunctional alpha-receptor as it is in animals made cretinism by radiothyroidectomy at birth. These results indicate that the beta thyroid hormone receptor has little if anything to do with normal brain development and that the effects of thyroid hormone on brain development are mediated by the alpha thyroid hormone receptor. Studies currently in progress are showing that although the baseline glucose utilization in cerebral structures is markedly reduced, the percent increases in their use of glucose evoked by neuronal functional activation is the same, indicating that the decreased baseline glucose utilization is due to diminished synaptic density but the remaining synapses are functionally normal.